Colorectal cancer (CRC) continues to be a major worldwide health issue, with elevated death rates linked to late stages of the illness. Immunotherapy has made significant progress in developing effective techniques to improve the immune system's capacity to identify and eradicate cancerous cells. This study examines the most recent advancements in CAR-T cell treatment and exosome-based immunotherapy for CRC. CAR-T cell therapy, although effective in treating blood cancers, encounters obstacles when used against solid tumours such as CRC. These obstacles include the presence of an immunosuppressive tumour microenvironment and a scarcity of tumour-specific antigens. Nevertheless, novel strategies like dual-receptor CAR-T cells and combination therapy involving cytokines have demonstrated promise in surmounting these obstacles. Exosome-based immunotherapy is a promising approach for targeted delivery of therapeutic drugs to tumour cells, with high specificity and minimal off-target effects. However, there are still obstacles to overcome in the field, such as resistance to treatment, adverse effects associated with the immune system, and the necessity for more individualised methods. The current research is focused on enhancing these therapies, enhancing the results for patients, and ultimately incorporating these innovative immunotherapeutic approaches into the standard treatment protocols for CRC.

In recent years, the role played by exosomes in lung diseases has been investigated. Exosomes have been shown to contribute to reductions in lung inflammation and pulmonary fibrosis. However, the role played by exosomes in pulmonary oxygen toxicity and the mechanism involved have not yet been reported. In the present work, we aimed to investigate the mechanism by which stem cell exosomes protect lung tissue and the potential molecular regulatory network involved. In this study, we employed single-cell RNA sequencing techniques to elucidate the unique cellular and molecular mechanisms underlying the progression of exosome therapy for pulmonary oxygen toxicity. We found changes in cell populations after exosome treatment, characterized by the expression of different molecular markers. We also integrated single-cell RNA sequencing (scRNA-seq) and bulk analysis to identify the protective effects of mesenchymal stem cell exosomes (MSC-Exos) in a mouse pulmonary oxygen toxicity (POT) model. scRNA-seq revealed dynamic shifts in the lung cellular composition after exosome treatment, including a reduction in inflammatory lymphoid cells (NK, B cells, CD8+ T, CD4+ T) and restored alveolar epithelial populations (AT1/AT2). A comprehensive gene expression analysis showed that inflammatory pathways associated with oxidative stress were significantly upregulated. In addition, our analysis of the intercellular interaction network revealed that there was a significant reduction in intercellular signal transduction in the POT group compared to the exosome-treated group. These results not only shed light on the unique cellular heterogeneity and potential pathogenesis following exosome therapy, but they also deepen our understanding of molecular pathophysiology and provide new avenues for targeted therapeutic strategies.

Exosomes are double-membrane vesicular nanoparticles in the category of extracellular vesicles, ranging in size from 30 to 150 nm, and are released from cells through a specific multi-step exocytosis process. Exosomes have emerged as promising tools for tissue repair due to their ability to transfer bioactive molecules that promote cell proliferation, differentiation, and tissue regeneration. However, the therapeutic application of exosomes is hindered by their rapid clearance from the body and limited retention at the injury site. To overcome these challenges, hydrogels, known for their high biocompatibility and porous structure, have been explored as carriers for exosomes. Hydrogels can provide a controlled release mechanism, prolonging the retention time of exosomes at targeted tissues, thus enhancing their therapeutic efficacy. This review focuses on the combination of different exosomes with hydrogels in the context of tissue repair. We first introduce the sources and functions of exosomes, particularly those from mesenchymal stem cells, and their roles in regenerative medicine. We then examine various types of hydrogels, highlighting their ability to load and release exosomes. Several strategies for encapsulating exosomes in hydrogels are discussed, including the impact of hydrogel composition and structure on exosome delivery efficiency. Finally, we review the applications of exosomes-loaded hydrogels in the repair of different tissues, such as skin, bone, cartilage, and nerve, and explore the challenges and future directions in this field. The combination of exosomes with hydrogels offers significant promise for advancing tissue repair strategies and regenerative therapies.

The aging population has led to a global issue of osteoarthritis (OA), which not only impacts the quality of life for patients but also poses a significant economic burden on society. While biotherapy offers hope for OA treatment, currently available treatments are unable to delay or prevent the onset or progression of OA. Recent studies have shown that as nanoscale bioactive substances that mediate cell communication, exosomes from stem cell sources have led to some breakthroughs in the treatment of OA and have important clinical significance. This paper summarizes the mechanism and function of stem cell exosomes in delaying OA and looks forward to the development prospects and challenges of exosomes.

Mesenchymal stem/stromal cells (MSCs) are a valuable source of paracrine factors, as they have a remarkable secretory capacity, and there is a sizeable knowledge base to develop industrial and clinical production protocols. Promising cell-free approaches for tissue regeneration and immunomodulation are driving research towards secretome applications, among which extracellular vesicles (EVs) are steadily gaining attention. However, the manufacturing and application of EVs is limited by insufficient yields, knowledge gaps, and low standardization. Facing these limitations, hydrogels represent a versatile three-dimensional (3D) culture platform that can incorporate extracellular matrix (ECM) components to mimic the natural stem cell environment in vitro; via these niche-mimicking properties, hydrogels can regulate MSCs' morphology, adhesion, proliferation, differentiation and secretion capacities. However, the impact of the hydrogel's architectural, biochemical and biomechanical properties on the production of EVs remains poorly understood, as the field is still in its infancy and the interdependency of culture parameters compromises the comparability of the studies. Therefore, this review summarizes and discusses the reported effects of hydrogel encapsulation and culture on the secretion of MSC-EVs. Considering the effects of cell-material interactions on the overall paracrine activity of MSCs, we identify persistent challenges from low standardization and process control, and outline future paths of research, such as the synergic use of hydrogels and bioreactors to enhance MSC-EV generation.

Peripheral nerve injury (PNI) as a common clinical issue that presents significant challenges for repair. Factors such as donor site morbidity from autologous transplantation, slow recovery of long-distance nerve damage, and deficiencies in local cytokines and extracellular matrix contribute to the complexity of effective PNI treatment. It is extremely urgent to develop functional nerve guidance conduits (NGCs) as substitutes for nerve autografts. We fabricate an aligned topological scaffold by combining the E-jet 3D printing and electrospinning to exert synergistic topographical cue for peripheral nerve regeneration. To address the limitation of NGCs with hollow lumens in repairing long-distance nerve defects, we modified the internal microenvironment by filling the lumen with umbilical cord-derived decellularized extracellular matrix (dECM) hydrogels and extracellular vesicles (EVs). This approach led to the development of a functional HE-NGC. Herein, the HE-NGCs provided obvious guidance and proliferation to SCs and PC12 in vitro due to the sustained-release effect of dECM hydrogels and the outstanding proliferation-promoting role of EVs. The HE-NGCs was surgically implanted in vivo to bridge 12-mm gap sciatic nerve defect in rats and it had a satisfactory effect in reestablishment of the sciatic nerve, including the recovery of motor functions and the myelination. Further studies revealed that HE-NGCs might promoted axon growth by activating the PI3K/Akt/mTOR and inhibiting the MAPK signaling pathways. These findings indicate that HE-NGCs effectively promote nerve regeneration, offering a promising strategy for applications in peripheral nerve repair. STATEMENT OF SIGNIFICANCE: This study introduces an approach using an E-jet 3D printing system to fabricate three-dimensional aligned scaffolds with varying gap sizes, optimizing the structure for Schwann cells migration. We present, for the first time, a comprehensive investigation into the effects of EVs derived from umbilical cord mesenchymal stem cells on Schwann cells behavior. By leveraging the natural extracellular matrix (ECM), we significantly enhanced the efficacy and longevity of EVs encapsulated within a dECM hydrogel. Our provided strategy involves utilizing EVs to support nerve cell migration and proliferation along aligned NGCs. As the dECM hydrogel degrades, EVs are gradually released, facilitating the deposition of new ECM and enabling the repair of nerve defects up to 12-mm in length.

In the intricate landscape of cellular communication, small extracellular vesicles (sEVs) originating from endosomes play crucial roles as mediators and have garnered significant attention in theranostics. Our understanding of sEV biogenesis largely stems from studies on cancer cells, which are vital for diagnostics. However, in therapeutics, where mesenchymal stromal cell (MSC)-derived sEVs are emerging as investigational new drugs, their biogenesis pathways remain largely unexplored. This article explores the parallel narratives of sEV biogenesis in cancer cells and stem cells, specifically using HeLa cells and MSCs as model cell lines. This study investigated the roles of key proteins-hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), signal-transducing adaptor molecule (STAM), tumor susceptibility gene 101 (TSG101), and ALG-2-interacting protein X (ALIX)-as identified in HeLa cells, in the context of MSC-sEV biogenesis. While these proteins show similarities across cell types, a discernible difference arises in their primary functions in regulating sEV biogenesis. The critical role of ALIX in MSC-sEV biogenesis, in particular, underscores its potential as a target for modulating sEVs' yield in regenerative therapies. Through this comparative analysis, we identified shared molecular signatures, offering insights to guide therapeutic interventions and unlock the regenerative potential of stem cells.

Extracellular vesicles (EVs) are taken up by most cells, however specific or preferential cell targeting remains a hurdle. This study aims to develop an EV that targets cells involved in inflammation, specifically those expressing intercellular adhesion molecule-1 (ICAM-1). To target these cells, we overexpress the ICAM-1 binding receptor "lymphocyte function-associated antigen-1" (LFA-1) in HEK293F cells, by sequential transfection of plasmids of the two LFA-1 subunits, ITGAL and ITGB2 (CD11a and CD18). The LFA-1 receptor was strongly overexpressed on the EVs released by the transfected cells. We further loaded these EVs with a therapeutic peptide, targeting myeloid differentiation primary response 88 (Myd88; EVMyd88), through a developed EV open-and-close procedure. Myd88 is a downstream common intracellular messenger for most TLR-receptors. EV expression of LFA-1 increases EV binding to ICAM-1-expressing cells, an effect that was dose-dependently inhibited by a specific neutralizing ICAM-1 antibody. Further, activated human endothelial cells treated with LFA-1 EVMyd88 had increased uptake of these EVs, resulting in dose-dependent inhibition of induced release of IL-8, presumably by targeting Myd88. We conclude that LFA-1-expressing EVMyd88 may be a candidate suitable for delivering therapeutic peptides in inflammatory diseases associated with TLR-activation.

To assess the therapeutic effects of mesenchymal stem cell (MSC)-derived exosome therapy on periodontal regeneration and identify treatment factors associated with enhanced periodontal regeneration in recent preclinical studies.

Searches were conducted in PubMed, Cochrane Library, EMBASE, and Web of Science databases until October 10, 2024. A risk of bias (ROB) assessment was performed using the SYRCLE tool. Osteogenic-related parameters were used as the primary outcome measures.

In total, 1360 articles were identified, of which 17 preclinical studies were based on MSC-derived exosome therapy, and they demonstrated a beneficial effect on BV/TV (SMD = 13.99; 95% Cl = 10.50, 17.48; p < 0.00001), CEJ-ABC (SMD = -0.22; 95% Cl = -0.31, -0.13; p < 0.00001), BMD (SMD = 0.29; 95% Cl = 0.14, 0.45; p = 0.0002), and Tp.Sp (SMD = -0.08; 95% Cl= -0.15, -0.02; p = 0.02) compared with the control group. However, no significant differences were observed in Tp.Th (SMD = 0.03; 95% CI = 0.00, 0.07; p = 0.09) between the exosome-treated group and control group. Additionally, subgroup analysis indicated that preconditioned exosomes (p = 0.03) significantly improved BV/TV. In contrast, there were no significant differences in the enhancement of BV/TV with respect to the application method (p = 0.29), application frequency (p = 0.10), treatment duration (p = 0.15), or source of MSCs (p = 0.31).

MSC-derived exosomes show great promise for enhancing the quality of periodontal regeneration. However, more standardized and robust trials are needed to reduce heterogeneity and bias across studies and to confirm the therapeutic parameters associated with the enhancement of periodontal regeneration by MSC-derived exosomes.

CRD42024546236.

Colorectal cancer (CRC) ranks as the third most common cancer worldwide and remains a major cause of cancer-related deaths, necessitating the development of innovative therapeutic approaches beyond conventional treatment modalities. Conventional therapies, such as radiation, chemotherapy, and surgery, are hindered by challenges like imprecise targeting, substantial toxicity, and the development of resistance. Exosome-driven nano-immunotherapy has emerged as a groundbreaking approach that leverages the natural properties of exosomes-cell-derived vesicles known for their role in intercellular communication-to deliver therapeutic agents with high precision and specificity. This approach utilizes the natural ability of exosomes to serve as natural nanocarriers for various biomolecules, such as proteins, nucleic acids, and lipids, enabling precise drug delivery and immune modulation. Exosomes offer distinct advantages compared to traditional drug delivery systems, including their biocompatibility, capability to traverse biological barriers, and suitability for personalized medicine approaches. We evaluate the effectiveness of exosome-based therapies in comparison to traditional approaches, emphasizing their ability to achieve precise delivery, minimize systemic toxicity, and enhance treatment results. Despite their promise, several challenges remain, including the standardization of exosome isolation and production, optimization of cargo loading techniques, and ensuring safety and efficacy in clinical applications. By overcoming these obstacles and leveraging the distinctive characteristics of exosomes, exosome-driven nano-immunotherapy presents a promising avenue for more efficient therapeutic interventions.

Mesenchymal stem cells (MSCs) are multilineage differentiating stromal cells with extensive immunomodulatory and anti-inflammatory properties. MSC-based therapy is widely used in the treatment of various pathologies, including bone and cartilage diseases, cardiac ischemia, diabetes, and neurological disorders. Along with MSCs, it is promising to study the therapeutic properties of exosomes derived from MSCs (MSC-Exo). A number of studies report that the therapeutic properties of MSC-Exo are superior to those of MSCs. In particular, MSC-Exo are used for tissue regeneration in various diseases, such as healing of skin wounds, cancer, coronary heart disease, lung injury, liver fibrosis, and neurological, autoimmune, and inflammatory diseases. In this regard, it is not surprising that the scientific community is interested in studying the therapeutic properties of MSCs and MSC-Exo in the treatment of psoriasis. This review summarizes the recent advancements from preclinical and clinical studies of MSCs and MSC-Exo in the treatment of psoriasis, and it also discusses their mechanisms of therapeutic action involved in the treatment of this disease.

Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as promising candidates for cell-free therapy in tissue regeneration. However, the native osteogenic and angiogenic capacities of MSC-Exos are often insufficient to repair critical-sized bone defects, and the underlying immune mechanisms remain elusive. Furthermore, achieving sustained delivery and stable activity of MSC-Exos at the defect site is essential for optimal therapeutic outcomes. Here, we extracted exosomes from osteogenically pre-differentiated human bone marrow mesenchymal stem cells (hBMSCs) by ultracentrifugation and encapsulated them in gelatin methacryloyl (GelMA) hydrogel to construct a composite scaffold. The resulting exosome-encapsulated hydrogel exhibited excellent mechanical properties and biocompatibility, facilitating sustained delivery of MSC-Exos. Osteogenic pre-differentiation significantly enhanced the osteogenic and angiogenic properties of MSC-Exos, promoting osteogenic differentiation of hBMSCs and angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, MSC-Exos induced polarization of Raw264.7 cells from a pro-inflammatory phenotype to an anti-inflammatory phenotype under simulated inflammatory conditions, thereby creating an immune microenvironment conducive to osteogenesis. RNA sequencing and bioinformatics analysis revealed that MSC-Exos activate the p53 pathway through targeted delivery of internal microRNAs and regulate macrophage polarization by reducing DNA oxidative damage. Our study highlights the potential of osteogenic exosome-encapsulated composite hydrogels for the development of cell-free scaffolds in bone tissue engineering.

Reconstruction of a full-thickness spongy urethra is difficult because a corpus spongiosum (CS) defect cannot be repaired using self-healing or substitution urethroplasty. Small extracellular vesicles (sEVs) secreted by urine-derived stem cells (USC-sEVs) strongly promote vascular regeneration. In this study, it is aimed to explore whether USC-sEVs promote the repair of CS defects. To prolong the in vivo effects of USC-sEVs, a void-forming photoinduced imine crosslinking hydrogel (vHG) is prepared and mixed with the USC-sEV suspension. vHG encapsulated with USC-sEVs (vHG-sEVs) is used to repair a CS defect with length of 1.5 cm and width of 0.8 cm. The results show that vHG-sEVs promote the regeneration and repair of CS defects. Histological analysis reveals abundant sinusoid-like vascular structures in the vHG-sEV group. Photoacoustic microscopy indicates that blood flow and microvascular structure of the defect area in the vHG-sEV group are similar to those in the normal CS group. This study confirms that the in situ-formed vHG-sEV patch appears to be a valid and promising strategy for repairing CS defects.

Stem cell derived small extracellular vesicles (sEVs) have emerged as promising nanomaterials for the repair of bone defects. However, low retention of sEVs affects their therapeutic effects. Clinically used natural substitute inorganic bovine bone mineral (Bio-Oss) bone powder lacks high compactibility and efficient osteo-inductivity that limit its clinical application in repairing large bone defects. In this study, a poly ethylene glycol/hyaluronic acid (PEG/HA) hydrogel was used to stabilize Bio-Oss and incorporate rat bone marrow stem cell-derived sEVs (rBMSCs-sEVs) to engineer a PEG/HA-Bio-Oss (PEG/HA-Bio) composite scaffold. Encapsulation and sustained release of sEVs in hydrogel scaffold can enhance the retention of sEVs in targeted area, achieving long-lasting repair effect. Meanwhile, synergistic administration of sEVs and Bio-Oss in cranial defect can improve therapeutic effects. The PEG/HA-Bio composite scaffold showed good mechanical properties and biocompatibility, supporting the growth of rBMSCs. Furthermore, sEVs enhancedin vitrocell proliferation and osteogenic differentiation of rBMSCs. Implantation of sEVs/PEG/HA-Bio in rat cranial defect model promotedin vivobone regeneration, suggesting the great potential of sEVs/PEG/HA-Bio composite scaffold for bone repair and regeneration. Overall, this work provides a strategy of combining hydrogel composite scaffold systems and stem cell-derived sEVs for the application of tissue engineering repair.

Alzheimer's disease (AD) poses a significant public health challenge, increasingly affecting patients' finances, mental health, and functional abilities as the global population ages. Stem cell-derived extracellular vesicles (SC-EVs) have emerged as a promising cell-free therapeutic approach for AD, although their precise mechanisms remain unclear. This meta-analysis aims to evaluate the effectiveness of SC-EVs in treating AD.

We systematically searched PubMed, EMBASE, and Web of Science databases up to December 31, 2023, identifying studies investigating SC-EVs therapy in AD rodent models. Outcome measures included Morris water maze and Y maze tests, β-amyloid pathology, and inflammatory markers. Statistical analyses utilized Stata 15.1 and R software.

This meta-analysis of 16 studies (2017-2023, 314 animals) demonstrates significant efficacy of SC-EVs therapy in AD models. Pooled analyses demonstrated that SC-EVs therapy significantly increased the learning function as measured by Morris water maze tests (MWM) by -1.83 (95% CI = -2.51 to -1.15, p < 0.0001), Y maze test by 1.66 (95% CI = 1.03 to 2.28, p < 0.0001), decreased Aβ plaques in the hippocampal by -2.10 (95% CI = -2.96 to -1.23, p < 0.0001), and proinflammatory cytokines Tumor necrosis factor alpha (TNFα) by -2.61 (95% CI = -4.87 to -0.35, p < 0.05), Interleukin-1 beta (IL-1β) by -2.37 (95% CI = -3.68 to -1.05, p < 0.001).

SC-EVs therapy shows promise in enhancing cognitive function and mitigating AD progression in preclinical models. Future research should focus on standardizing methodologies and comparing SC-EVs isolation techniques and dosing strategies to facilitate clinical translation.

Extracellular vesicles (EV) are a heterogeneous group of lipid particles excreted by cells. They play an important role in regeneration, development, inflammation, and cancer progression, together with the extracellular matrix (ECM), which they constantly interact with. In this review, we discuss direct and indirect interactions of EVs and the ECM and their impact on different physiological processes. The ECM affects the secretion of EVs, and the properties of the ECM and EVs modulate EVs' diffusion and adhesion. On the other hand, EVs can affect the ECM both directly through enzymes and indirectly through the modulation of the ECM synthesis and remodeling by cells. This review emphasizes recently discovered types of EVs bound to the ECM and isolated by enzymatic digestion, including matrix-bound nanovesicles (MBV) and tissue-derived EV (TiEV). In addition to the experimental studies, computer models of the EV-ECM-cell interactions, from all-atom models to quantitative pharmacology models aiming to improve our understanding of the interaction mechanisms, are also considered. STATEMENT OF SIGNIFICANCE: Application of extracellular vesicles in tissue engineering is an actively developing area. Vesicles not only affect cells themselves but also interact with the matrix and change it. The matrix also influences both cells and vesicles. In this review, different possible types of interactions between vesicles, matrix, and cells are discussed. Furthermore, the united EV-ECM system and its regulation through the cellular activity are presented.

Osteoarthritis (OA) is a leading cause of pain and disability worldwide in elderly people. There is a critical need to develop novel therapeutic strategies that can effectively manage pain and disability to improve the quality of life for older people. Mesenchymal stem cells (MSCs) have emerged as a promising cell-based therapy for age-related disorders due to their multilineage differentiation and strong paracrine effects. Notably, MSC-derived exosomes (MSC-Exos) have gained significant attention because they can recapitulate MSCs into therapeutic benefits without causing any associated risks compared with direct cell transplantation. These exosomes help in the transport of bioactive molecules such as proteins, lipids, and nucleic acids, which can influence various cellular processes related to tissue repair, regeneration, and immune regulation. In this review, we have provided an overview of MSC-Exos as a considerable treatment option for osteoarthritis. This review will go over the underlying mechanisms by which MSC-Exos may alleviate the pathological hallmarks of OA, such as cartilage degradation, synovial inflammation, and subchondral bone changes. Furthermore, we have summarized the current preclinical evidence and highlighted promising results from in vitro and in vivo studies, as well as progress in clinical trials using MSC-Exos to treat OA.

Introduction: We hypothesized extracellular vesicles (EVs) from preconditioned human-induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) attenuate LPS-induced acute lung injury (ALI) and endotoxemia. Methods: iMSCs were incubated with cell stimulation cocktail (CSC) and EVs were isolated. iMSC-EVs were characterized by size and EV markers. Biodistribution of intratracheal (IT), intravenous, and intraperitoneal injection of iMSC-EVs in mice was examined using IVIS. Uptake of iMSC-EVs in lung tissue, alveolar macrophages, and RAW264.7 cells was also assessed. C57BL/6 mice were treated with IT/IP iMSC-EVs or vehicle ± IT/IP LPS to induce ALI/acute respiratory distress syndrome and endotoxemia. Lung tissues, plasma, and bronchoalveolar lavage fluid (BALF) were harvested at 24 h. Lung histology, BALF neutrophil/macrophage, cytokine levels, and total protein concentration were measured to assess ALI and inflammation. Survival studies were performed using IP LPS in mice for 3 days. Results: iMSC-EV route of administration resulted in differential tissue distribution. iMSC-EVs were taken up by alveolar macrophages in mouse lung and cultured RAW264.7 cells. IT LPS-treated mice demonstrated marked histologic ALI, increased BALF neutrophils/macrophages and protein, and increased BALF and plasma TNF-α/IL-6 levels. These parameters were attenuated by 2 h before or 2 h after treatment with IT iMSC-EVs in ALI mice. Interestingly, the IT LPS-induced increase in IL-10 was augmented by iMSC-EVs. Mice treated with IP LPS showed increases in TNF-α and IL-6 that were downregulated by iMSC-EVs and LPS-induced mortality was ameliorated by iMSC-EVs. Administration of IT iMSC-EVs 2 h after LPS downregulated the increase in proinflammatory cytokines (TNF-α/IL-6) by LPS and further increased IL-10 levels. Conclusions: iMSC-EVs attenuate the inflammatory effects of LPS on cytokine levels in ALI and IP LPS in mice. LPS-induced mortality was improved with administration of iMSC-EVs.

Endogenous stem cell homing refers to the transport of endogenous mesenchymal stem cells (MSCs) to damaged tissue. The paradigm of using well-designed biomaterials to induce resident stem cells to home in to the injured site while coordinating their behavior and function to promote tissue regeneration is known as endogenous regenerative medicine (ERM). ERM is a promising new avenue in regenerative therapy research, and it involves the mobilizing of endogenous stem cells for homing as the principal means through which to achieve it. Comprehending how mesenchymal stem cells home in and grasp the influencing factors of mesenchymal stem cell homing is essential for the understanding and design of tissue engineering. This review summarizes the process of MSC homing, the factors influencing the homing process, analyses endogenous stem cell homing studies of interest in the field of skin tissue repair, explores the integration of endogenous homing promotion strategies with cellular therapies and details tissue engineering strategies that can be used to modulate endogenous homing of stem cells. In addition to providing more systematic theories and ideas for improved materials for endogenous tissue repair, this review provides new perspectives to explore the complex process of tissue remodeling to enhance the rational design of biomaterial scaffolds and guide tissue regeneration strategies.

Diabetic wounds are among the most common complications of diabetes mellitus and their healing process can be delayed due to persistent inflammatory reactions, bacterial infections, damaged vascularization and impaired cell proliferation, which casts a blight on patients'health and quality of life. Therefore, new strategies to accelerate diabetic wound healing are being positively explored. Exosomes derived from mesenchymal stem cells (MSC-Exos) can inherit the therapeutic and reparative abilities of stem cells and play a crucial role in diabetic wound healing. However, poor targeting, low concentrations of therapeutic molecules, easy removal from wounds and limited yield of MSC-Exos are challenging for clinical applications. Bioengineering techniques have recently gained attention for their ability to enhance the efficacy and yield of MSC-Exos. In this review, we summarise the role of MSC-Exos in diabetic wound healing and focus on three bioengineering strategies, namely, parental MSC-Exos engineering, direct MSC-Exos engineering and MSC-Exos combined with biomaterials. Furthermore, the application of bioengineered MSC-Exos in diabetic wound healing is reviewed. Finally, we discuss the future prospects of bioengineered MSC-Exos, providing new insights into the exploration of therapeutic strategies.

Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function is mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include 'priming' MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Furthermore, clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.

Exosomes, a category of extracellular vesicle (EV), are phospholipid bilayer structures ranging from 30 to 150 nm, produced by various organisms through the endosomal pathway. Recent studies have established the utilization of exosomes as nanocarriers for drug distribution across various therapeutic areas including cancer, acute liver injury, neuroprotection, oxidative stress, inflammation, etc. The importance of plant-derived exosomes and exosome vesicles derived from mammalian cells or milk, loaded with potent plant bioactives for various therapeutic indications are discussed along with insights into future perspectives. Moreover, this review provides a detailed understanding of exosome biogenesis, their composition, classification, stability of different types of exosomes, and different routes of administration along with the standard techniques used for isolating, purifying, and characterizing exosomes.

The growing understanding of the role of extracellular vesicles (EVs) in embryo-maternal communication has sparked considerable interest in their therapeutic potential within assisted reproductive technology, particularly in enhancing implantation success. However, the major obstacle remains the large-scale production of EVs, and there is still a gap in understanding how different culture systems affect the characteristics of the EVs. In the current study, trophoblast analogue human chorionic carcinoma cell line was cultivated in both conventional monolayer culture (2D) and as spheroids in suspension culture (3D) and how the cell growth environment affects the physical, biochemical and cellular signalling properties of EVs produced by them was studied. Interestingly, the 3D system was more active in secreting EVs compared to the 2D system, while no significant differences were observed in terms of morphology, size, and classical EV protein marker expression between EVs derived from the two culture systems. There were substantial differences in the proteomic cargo profile and cellular signalling potency of EVs derived from the two culture systems. Notably, 2D EVs were more potent in inducing a cellular response in endometrial epithelial cells (EECs) compared to 3D EVs. Therefore, it is essential to recognize that the biological activity of EVs depends not only on the cell of origin but also on the cellular microenvironment of the parent cell. In conclusion, caution is warranted when selecting an EV production platform, especially for assessing the functional and therapeutic potential of EVs through in vitro studies.

Human bone marrow-derived stem cells (hBMDSCs) are well characterized mediators of tissue repair and regeneration. An increasing body of evidence indicates that these cells exert their therapeutic effects largely through their paracrine actions rather than clonal expansion and differentiation. Here we studied the role of microRNAs (miRNAs) present in extracellular vesicles (EVs) from hBMDSCs in tissue regeneration and cell differentiation targeting endometrial stromal fibroblasts (eSF).

Extracellular vesicles (EVs) are isolated from hBMDSCs, characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) techniques. Extracted total RNA from EVs was subjected to RNA seq analysis. Transfection and decidualization studies were carried out in endometrial stromal fibroblasts (eSF). Gene expression was analyzed by qRTPCR. Unpaired t-test with Welch's correction was used for data analysis between two groups.

We identified several microRNAs (miRNAs) that were highly expressed, including miR-21-5p, miR-100-5p, miR-143-3p and let7. MiR-21 is associated with several signaling pathways involved in tissue regeneration, quiescence, cellular senescence, and fibrosis. Both miR-100-5p and miR-143-3p promoted cell proliferation. MiR-100-5p specifically promoted regenerative processes by upregulating TGF-ß3, VEGFA, MMP7, and HGF. MiR-100-5p blocked differentiation or decidualization as evidenced by morphologic changes and downregulation of decidualization mediators including HOXA10, IGFBP1, PRL, PR-B, and PR.

EVs delivered to tissues by hBMDSCs contain specific miRNAs that prevent terminal differentiation and drive repair and regeneration. Delivery of microRNAs is a novel treatment paradigm with the potential to replace BMDSCs in cell-free regenerative therapies.

Extracellular vesicles (EVs) are natural particles secreted by living cells, which hold significant potential for various therapeutic applications. Native EVs have specific components and structures, allowing them to cross biological barriers, and circulate in vivo for a long time. Native EVs have also been bioengineered to enhance their therapeutic efficacy and targeting affinity. Recently, the therapeutic potential of surface-engineered EVs has been explored in the treatment of tumors, autoimmune diseases, infections and other diseases by ongoing research and clinical trials. In this review, we will introduce the modified methods of engineered EVs, summarize the application of engineered EVs in preclinical and clinical trials, and discuss the opportunities and challenges for the clinical translation of surface-engineered EVs.

The development of static hydrogels as an optimal choice for bone tissue engineering (BTE) remains a difficult challenge primarily due to the intricate nature of bone healing processes, continuous physiological functions, and pathological changes. Hence, there is an urgent need to exploit smart hydrogels with programmable properties that can effectively enhance bone regeneration. Increasing evidence suggests that photoresponsive hydrogels are promising bioscaffolds for BTE due to their advantages such as controlled drug release, cell fate modulation, and the photothermal effect. Here, we review the current advances in photoresponsive hydrogels. The mechanism of photoresponsiveness and its advanced applications in bone repair are also elucidated. Future research would focus on the development of more efficient, safer, and smarter photoresponsive hydrogels for BTE. This review is aimed at offering comprehensive guidance on the trends of photoresponsive hydrogels and shedding light on their potential clinical application in BTE.

Bone-marrow-derived mesenchymal stromal (stem) cells [also called MSC(M)] and their extracellular vesicles (EVs) are considered a potentially innovative form of therapy for traumatic brain injury (TBI). Nevertheless, their application to TBI particularly remains preclinical, and the effects of these cells remain unclear and controversial. Therefore, an updated meta-analysis of preclinical studies is necessary to assess the effectiveness of MSC(M) and MSC(M) derived EVs in clinical trials.

The following databases were searched (to December 2022): PubMed, Web of Science, and Embase. In this study, we measured functional outcomes based on the modified neurological severity score (mNSS), cognitive outcomes based on the Morris water maze (MWM), and histopathological outcomes based on lesion volume. A random effects meta-analysis was conducted to evaluate the effect of mNSS, MWM, and lesion volume.

A total of 2163 unique records were identified from our search, with Fifty-five full-text articles satisfying inclusion criteria. A mean score of 5.75 was assigned to the studies' quality scores, ranging from 4 to 7. MSC(M) and MSC(M) derived EVs had an overall positive effect on the mNSS score and MWM with SMDs -2.57 (95 % CI -3.26; -1.88; p < 0.01) and - 2.98 (95 % CI -4.21; -1.70; p < 0.01), respectively. As well, MSC(M) derived EVs were effective in reducing lesion volume by an SMD of - 0.80 (95 % CI -1.20; -0.40; p < 0.01). It was observed that there was significant variation among the studies, but further analyses could not determine the cause of this heterogeneity.

MSC(M) and MSC(M) derived EVs are promising treatments for TBI in pre-clinical studies, and translation to the clinical domain appears warranted. Besides, large-scale trials in animals and humans are required to support further research due to the limited sample size of MSC(M) derived EVs.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of cancer, in particular lung cancer, while the introduction of predictive biomarkers from liquid biopsies has emerged as a promising tool to achieve an effective and personalized therapy response. Important progress has also been made in the molecular characterization of extracellular vesicles (EVs) and circulating tumor cells (CTCs), highlighting their tremendous potential in modulating the tumor microenvironment, acting on immunomodulatory pathways, and setting up the pre-metastatic niche. Surface antigens on EVs and CTCs have proved to be particularly useful in the case of the characterization of potential immune escape mechanisms through the expression of immunosuppressive ligands or the transport of cargos that may mitigate the antitumor immune function. On the other hand, novel approaches, to increase the expression of immunostimulatory molecules or cargo contents that can enhance the immune response, offer premium options in combinatorial clinical strategies for precision immunotherapy. In this review, we discuss recent advances in the identification of immune checkpoints using EVs and CTCs, their potential applications as predictive biomarkers for ICI therapy, and their prospective use as innovative clinical tools, considering that CTCs have already been approved by the Food and Drug Administration (FDA) for clinical use, but providing good reasons to intensify the research on both.

Bioactive material concepts for targeted therapy have been an important research focus in regenerative medicine for years. The aim of this study was to investigate a proof-of-concept composite structure in the form of a membrane made of natural silk fibroin (SF) and extracellular vesicles (EVs) from gingival fibroblasts. EVs have multiple abilities to act on their target cell and can thus play crucial roles in both physiology and regeneration. This study used pH neutral, degradable SF-based membranes, which have excellent cell- and tissue-specific properties, as the carrier material. The characterization of the vesicles showed a size range between 120 and 180 nm and a high expression of the usual EV markers (e.g. CD9, CD63 and CD81), measured by nanoparticle tracking analysis (NTA) and single-EV flow analysis (IFCM). An initial integration of the EVs into the membrane was analyzed using scanning and transmission electron microscopy (SEM and TEM) and vesicles were successfully detected, even if they were not homogeneously distributed in the membrane. Using direct and indirect tests, the cytocompatibility of the membranes with and without EVs could be proven and showed significant differences compared to the toxic control (p < 0.05). Additionally, proliferation of L929 cells was increased on membranes functionalized with EVs (p > 0.05).

Objectives: The aim of this study was to conduct a bibliometric analysis of the literature on stem cell treatment for spinal cord injury to gain an intuitive understanding of how the field is progressing, discover topics of interest, and determine what development trends are emerging in this field. Background: Spinal cord injury and its complications often cause an enormous economic burden, and postinjury repair and treatment have always been challenging in clinical and scientific research. Stem cell therapy for spinal cord injury can prevent immune rejection and induce the release of neuroprotective and anti-inflammatory factors to reduce the production of stress-related proteins, reactive oxygen species, and inflammatory reactions. Methods: We analyzed the number and quality of publications in the field of stem cell therapy in spinal cord injury between 2018.01.01 and 2023.06.30 in the core collection database of Web of Science. CiteSpace and VOSviewer were used to sort and summarize these studies by country, institution, authors' publications, and collaborative networks. In addition, the research topics of interest were identified and summarized. Results: This study ultimately included 2,150 valid papers, with the number of publications showing a gradual upward trend. The country, institution, author and journal with the greatest number of publications and citations are China, the Chinese Academy of Sciences, Dai JW, and the International Journal of Molecular Sciences, respectively. The top three high-frequency keyword clusters were hereditary paraplegia, reactive astrocytes and tissue engineering. Conclusion: With the help of visual analysis, we identified general trends and research topics of interest in the field of spinal cord injury over the last 5 years. Our findings suggest that stem cell transplantation for spinal cord injury and exosome therapy may be a focus of future research. This study provides a foundation for future research on stem cell therapy as well as clinical efforts in this field.

Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.

Mesenchymal stromal/stem cell derived-extracellular vesicles (MSC-EVs) have gained interest as drug delivery nanoparticles, having immunoregulatory and potentiating tissue repair property. To maintain growth of MSCs and obtain pure MSC-derived EVs, the culture media should contain fetal bovine serum (FBS) devoid of EVs, as the presence of FBS EVs confounds the properties of MSC-EVs. Therefore, we tested three methods: 18h ultracentrifugation (UC) and ultrafiltration (UF), which are common FBS EV depletion methods in current MSC-EV research, and polyethylene glycol (PEG) precipitation to obtain three EV depleted FBS (EVdFBS) batches, and compared them to FBS and commercial (Com) EVdFBS on human adipose stem cell (hADSC) growth, differentiation, enrichment of EVs in hADSC supernatant and their biological function on collagen metabolism. Our comparative study showed UC and UF vary in terms of depletion efficiency and do not completely deplete EVs and affects the growth-promoting quality of FBS. Specifically, FBS EV depletion was comparable between PEG (95.6%) and UF (96.6%) but less by UC (82%), as compared to FBS. FBS protein loss was markedly different among PEG (47%), UF (87%), and UC (51%), implying the ratio of EV depletion over protein loss was PEG (2.03), UF (1.11), and UC (1.61). A significant decrease of TGFβ/Smad signaling, involving in MSC growth and physiology, was observed by UF. After 96 hours of exposure to 5% FBS or 5% four different EVdFBS cell growth media, the osteogenesis ability of hADSCs was not impaired but slightly lower mRNA expression level of Col2a observed in EVdFBS media during chondrogenesis. In consistent with low confluency of hADSCs observed by optical microscope, cell proliferation in response to 5% UF EVdFBS media was inhibited significantly. Importantly, more and purer ADSCs EVs were obtained from ADSCs cultured in 5% PEG EVdFBS media, and they retained bioactive as they upregulated the expression of Col1a1, TIMP1 of human knee synovial fibroblast. Taken together, this study showed that PEG precipitation is the most efficient method to obtain EV depleted FBS for growth of MSCs, and to obtain MSC EVs with minimal FBS EV contamination.

The fast-growing pace of regenerative medicine research has allowed the development of a range of novel approaches to tissue engineering applications. Until recently, the main points of interest in the majority of studies have been to combine different materials to control cellular behavior and use different techniques to optimize tissue formation, from 3-D bioprinting to in situ regeneration. However, with the increase of the understanding of the fundamentals of cellular organization, tissue development, and regeneration, has also come the realization that for the next step in tissue engineering, a higher level of spatiotemporal control on cell-matrix interactions is required. It is proposed that the combination of artificial cell research with tissue engineering could provide a route toward control over complex tissue development. By equipping artificial cells with the underlying mechanisms of cellular functions, such as communication mechanisms, migration behavior, or the coherent behavior of cells depending on the surrounding matrix properties, they can be applied in instructing native cells into desired differentiation behavior at a resolution not to be attained with traditional matrix materials.

Adipose-derived mesenchymal stem cell (ADSC)-based therapies have been utilized for cartilage regeneration because of their multi-lineage differentiation ability. However, commonly used cartilage inducers such as the transforming growth factor beta-3 (TGF-β3) may be prone to cartilage dedifferentiation and hypertrophy. The directional differentiation of elastic cartilage is limited nowadays. Extracellular vesicles (EVs) have been reported to influence the specific differentiation of mesenchymal stem cells (MSCs) by reflecting the composition of the parental cells. However, the role of auricular chondrogenic-derived EVs (AC-EVs) in elastic chondrogenic differentiation of ADSCs has not yet been reported.

AC-EVs isolated from the external ears of swine exhibited a positive effect on cell proliferation and migration. Furthermore, AC-EVs efficiently promoted chondrogenic differentiation of ADSCs in pellet culture, as shown by the elevated levels of COL2A1, ACAN, and SOX-9 expression. Moreover, there was a significantly higher expression of elastin and a lower expression of the fibrotic marker COL1A1 in comparison with that achieved with TGF-β3. The staining results demonstrated that AC-EVs promoted the deposition of cartilage-specific matrix, which is in good concordance with the real-time polymerase chain reaction (RT-PCR) results.

Auricular chondrogenic-derived EVs are a crucial component in elastic chondrogenic differentiation and other biological behaviors of ADSCs, which may be a useful ingredient for cartilage tissue engineering and external ear reconstruction.

This journal requires that authors 42 assign a level of evidence to each submission to which 43 Evidence-Based Medicine rankings are applicable. This 44 excludes Review Articles, Book Reviews, and manuscripts 45 that concern Basic Science, Animal Studies, Cadaver 46 Studies, and Experimental Studies. For a full description of 47 these Evidence-Based Medicine ratings, please refer to the 48 Table oôf Contents or the online Instructions to Authors 49 www.springer.com/00266 .

Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function can be mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include 'priming' MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a serious clinical syndrome with a high morbidity and mortality. Presently, therapeutic approaches for ALI/ARDS primarily revolve around symptomatic supportive care encompassing mechanical ventilation and fluid management. Regrettably, the prognosis for most ALI/ARDS patients remains bleak due to the absence of effective treatment strategies. Even survivors of ALI/ARDS may have long-term pulmonary dysfunction and cognitive impairment. The quality of life has been seriously compromised. The emergence of mesenchymal stem cells (MSCs) and their exosomes has opened up an expansive realm of potential and optimism for addressing the plight of ALI/ARDS patients, as MSCs and their derived exosomes exhibit multifaceted capabilities, including anti-inflammatory properties, facilitation of tissue repair and regeneration, and apoptosis inhibition. Therefore, future research should focus on the possible mechanisms of MSCs and their derived exosomes for the treatment of ALI/ARDS and open up new avenues for their clinical applications.

The potential of perinatal tissues to provide cellular populations to be used in different applications of regenerative medicine is well established. Recently, the efforts of researchers are being addressed regarding the evaluation of cell products (secreted molecules or extracellular vesicles, EVs) to be used as an alternative to cellular infusion. The data regarding the effective recapitulation of most perinatal cells' properties by their secreted complement point in this direction. EVs secreted from perinatal cells exhibit key therapeutic effects such as tissue repair and regeneration, the suppression of inflammatory responses, immune system modulation, and a variety of other functions. Although the properties of EVs from perinatal derivatives and their significant potential for therapeutic success are amply recognized, several challenges still remain that need to be addressed. In the present review, we provide an up-to-date analysis of the most recent results in the field, which can be addressed in future research in order to overcome the challenges that are still present in the characterization and utilization of the secreted complement of perinatal cells and, in particular, mesenchymal stromal cells.

Extracellular vesicles (EVs) have emerged as a valuable and promising research field in eye diseases. However, there are few bibliometric studies in this area. The purpose of this study was to employ bibliometric analysis to visualize the research hotspots and trends of EVs in eye diseases and provide researchers with new perspectives for further studies.

Articles and reviews on EVs in eye diseases published between January 1, 2003 and December 31, 2022 were retrieved from the Web of Science Core Collection. Qualitative and quantitative analysis was performed using Microsoft Excel and CiteSpace software.

In total, 790 articles were included in the analysis. Over the past 2 decades, there has been a significant increase in the number of publications on the study of EVs in eye diseases. The United States, China, and Italy made the most significant contributions to this field. The Chinese Academy of Sciences was the most productive institution, and International Journal of Molecular Sciences published the most number of articles. Proceedings of the National Academy of Sciences of the United States of America had the highest citation frequency. Beit-Yannai E had the highest output and Thery C had the highest average citation frequency among authors. The analysis of keywords revealed that the neuroprotective effects of stem cell-derived EVs and biomarkers of eye diseases are current research hotspots and frontiers in this field.

This study provides a scientific perspective on EVs in eye diseases and provides valuable information for researchers to detect current research conditions, hotspots, and emerging trends for further study.

The pathogenesis of atopic dermatitis (AD) is multifactorial, including immune dysregulation and epidermal barrier defects, and a novel therapeutic modality that can simultaneously target multiple pathways is needed. We investigated the therapeutic effects of exosomes (IFN-γ-iExo) secreted from IFN-γ-primed induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) in mice with Aspergillus fumigatus-induced AD. IFN-γ-iExo was epicutaneously administered to mice with AD-like skin lesions. The effects of IFN-γ-iExo treatment were investigated through clinical scores, transepidermal water loss (TEWL) measurements, and histopathology. To elucidate the therapeutic mechanism, we used an in vitro model of human keratinocyte HaCaT cells stimulated with IL-4 and IL-13 and performed extensive bioinformatics analysis of skin mRNA from mice. The expression of indoleamine 2,3-dioxygenase was higher in IFN-γ primed iMSCs than in iMSCs. In human keratinocyte HaCaT cells, treatment with IFN-γ-iExo led to decreases in the mRNA expression of thymic stromal lymphopoietin, IL-25, and IL-33 and increases in keratin 1, keratin 10, desmoglein 1, and ceramide synthase 3. IFN-γ-iExo treatment significantly improved clinical and histological outcomes in AD mice, including clinical scores, TEWL, inflammatory cell infiltration, and epidermal thickness. Bioinformatics analysis of skin mRNA from AD mice showed that IFN-γ-iExo treatment is predominantly involved in skin barrier function and T cell immune response. Treatment with IFN-γ-iExo improved the clinical and histological outcomes of AD mice, which were likely mediated by restoring proper skin barrier function and suppressing T cell-mediated immune response.

Impairment of immune tolerance might cause autologous tissue damage or overactive immune response against non-pathogenic molecules. Although autoimmune disease and allergy have complicated pathologies, the current strategies have mainly focused on symptom amelioration or systemic immunosuppression which can lead to fatal adverse events. The induction of antigen-specific immune tolerance may provide therapeutic benefits to autoimmune disease and allergic response, while reducing nonspecific immune adverse responses. Diverse nanomaterials have been studied to induce antigen-specific immune tolerance therapy. This review will cover the immunological background of antigen-specific tolerance, clinical importance of antigen-specific immune tolerance, and nanomaterials designed for autoimmune and allergic diseases. As nanomaterials for modulating immune tolerances, lipid-based nanoparticles, polymeric nanoparticles, and biological carriers have been covered. Strategies to provide antigen-specific immune tolerance have been addressed. Finally, current challenges and perspectives of nanomaterials for antigen-specific immune tolerance therapy will be discussed.

Human mesenchymal stem cells (MSCs) are therapeutic for clinical applications because of their excellent immunomodulatory and multiple lineage differentiation abilities at tissue injury sites. However, insufficient number of cells and lack of regenerative properties during in vitro expansion still limit the clinical applicability of MSC therapies. Here, we demonstrated a preconditioning strategy with trophoblast stem cell-derived extracellular vesicles (TSC-EVs) to boost the proliferation and regenerative capacity of MSCs.

We employed cell proliferation analyses such as CCK8 and BrdU assays to determine the proliferation-promoting role of TSC-EVs on MSCs. Osteogenic effects of TSC-EVs on MSCs were assessed by alkaline phosphatase (ALP) activity, calcium assays, and calvarial bone defect animal models. For skin regenerative effects, skin wound mice model was exploited to analyze wound-healing rate in this study, as well as immunofluorescence and histological staining evaluates. We also performed the small RNA profiling and RNA-sequencing analyzes to understand the cellular mechanism of TSC-EVs on MSCs.

TSC-EVs significantly promoted MSC proliferation under xeno-free conditions and facilitated the therapeutic effects of MSCs, including osteogenesis, anti-senescence, and wound healing. Transcriptomic analysis also provided evidence that specific microRNAs in TSC-EVs and differentially expressed genes (DEGs) in TSC-EV-treated MSCs showed the possibility of TSC-EVs triggering the regenerative abilities of MSCs with cytokine interaction. Hence, we found that NGF/Akt signaling mediated the regenerative effects of TSC-EVs on MSCs as a particular cellular signaling pathway.

The results of this study demonstrated the functional properties of TSC-EVs on MSCs for MSC-based therapeutic applications, suggesting that TSC-EVs may serve as a potential preconditioning source for MSC therapy in the clinical field of regenerative medicine.